tbuckley/cabot-search huggingface dataset:
Clinical efficacy of daratumumab (DARA)-based second line therapy after DARA-containing and DARA-free induction therapies in multiple myeloma: A single center experience.
Authors: Amanda Ciardiello, Neha Korde, Malin Hultcrantz, Hani Hassoun, Sham Mailankody, Urvi A Shah, Sydney X. Lu, Dhwani Patel, Kylee Maclachlan, Oscar Boutros Lahoud, Gunjan L. Shah, Michael Scordo, David J. Chung, Heather Jolie Landau, Sergio Giralt, Andriy Derkach, Saad Zafar Usmani, Alexander M. Lesokhin, Carlyn Rose Co Tan
Journal: Journal of Clinical Oncology (2022)

e20005 Background: DARA has been FDA approved for newly diagnosed multiple myeloma (NDMM) in combination with lenalidomide/dexamethasone (Rd), bortezomib/melphalan/dex, and bortezomib/thalidomide/dex since 2018. With the increase use of DARA combinations in NDMM, understanding the role of DARA retreatment at relapse needs to be examined in clinical practice. Herein, we describe a single institution experience of the efficacy of DARA-based retreatment as second line of therapy (LOT2) for patients (pts) who received DARA-based induction compared to DARA-free induction regimens. Methods: Thirty-three pts treated with DARA-based LOT2 at MSK from 1/2015 to 9/2021 were included in this retrospective analysis. Primary endpoint was overall response rate (ORR; ≥PR by IMWG criteria). Discrete patient characteristics were summarized by frequency (percentage) and continuous characteristics were summarized by median (IQR). Progression free survival (PFS) was evaluated by Kaplan-Meier method. Results: Two cohorts were identified based on prior DARA exposure: cohort 1 (N=6) received DARA-based induction without meeting DARA-refractory criteria and cohort 2 (N=27) had carfilzomib and Rd (KRd) induction (Table). Median follow-up was 13.8 and 14.5 months for cohorts 1 and 2, respectively. In cohort 1, 5 pts received DARA-KRd and 1 had DRd as first line therapy (LOT1). Median time between last dose of DARA in LOT1 and first dose of DARA in LOT2 was 17.5 months (IQR 12.1-19.8). ORR were 83% and 79% for cohorts 1 and 2, respectively. In cohort 1, ORR comprised of 1 sCR, 1 VGPR, and 3 PR. For cohort 2, there were 5 sCR/CR, 7 VGPR, and 9 PR. Median PFS was not reached in cohort 1 and 16.2 months in cohort 2. Conclusions: In a cohort of pts retreated with DARA after DARA-based induction, our findings suggest that DARA-exposed MM pts may derive benefit from DARA retreatment in subsequent lines of therapy similarly to pts who were DARA-naïve prior to DARA-based LOT2. Longer follow-up is needed to assess survival outcomes. In addition, larger confirmatory studies are warranted to further characterize response characteristics of DARA combinations in LOT2, especially as DARA-based therapy is increasingly used in treating NDMM. [Table: see text]
Hepatic arterial infusion chemotherapy with oxaliplatin plus raltitrexed versus oxaliplatin plus fluorouracil in intermediate and advanced hepatocellular carcinoma: A retrospective study.
Authors: Mengya Zang, Qi Li, Xiaoyun Hu, Guosheng Yuan, Rong Li, Yabing Guo, Jinzhang Chen
Journal: Journal of Clinical Oncology (2022)

e16166 Background: Hepatic arterial infusion chemotherapy (HAIC) showed promising outcomes for advanced hepatocellular carcinoma (HCC) and was recommended in patients with advanced HCC in Asia. HAIC with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX) was most commonly used in China. However, Continuous infusion (over 46 hours) with fluorouracil was inconvenient for arterial infusion. Raltitrexed, another antimetabolic drug with long plasma concentrations half-life, could be used in short infusions. HAIC with raltitrexed plus oxaliplatin (RALOX) was reported to be effective and safe in HCC. This study aimed to compare efficacy and safety of HAIC with raltitrexed plus oxaliplatin versus oxaliplatin plus fluorouracil in intermediate and advanced HCC. Methods: Sixty-six patients with intermediated and advanced HCC were included in this retrospective study between March 2019 and November 2020. Thirty-three patients were treated with HAIC of FOLFOX (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , 5-fluorouracilbolus 400 mg/m 2 on day 1, and 5-fluorouracil infusion 2400 mg/m 2 for 46 h, every 3 weeks). Another thirty-three patients received HAIC of RALOX (oxaliplatin 100 mg/m 2 , raltitrexed3 mg/m 2 , every 3 weeks). Objective response rate (ORR), diseases control rate (DCR), progression-free survival (PFS) and treatment-related adverse events were analyzed. Results: The ORR was both 33.3% in the FOLFOX group and RALOX group per RECIST 1.1 criteria ( P = 1.00). The DCR was 90.9% and 87.9% in the FOLFOX group and RALOX group, respectively ( P = 1.00). The median PFS was 10.7 months in the FOLFOX group versus 7.9 months in the RALOX group ( P= 0.251). Grade 3/4 treatment-related adverse events were comparable between the two groups, including neutropenia, thrombocytopenia, elevated aminotransferase level and nausea. Conclusions: The efficacy and safety of HAIC with raltitrexed plus oxaliplatin was comparable to HAIC with oxaliplatin plus fluorouracil in intermediate and advanced HCC.
To conquer cervical and breast cancer in little charted waters: Synergistic and integrated approaches to identify early breast and cervical cancer in Cameroon.
Authors: Patrick Mbah Okwen, Maryanne Zithem Mbangsi, Kinlabel Tetamiyaka Tezok Okwen
Journal: Journal of Clinical Oncology (2022)

e17510 Background: Across Africa, several governments have put in place policies to promote prevention of cervical and breast cancers. (Njunguna 2020, Njiru 2013, WHO 2017) These include routine screening at consultations, sensitization programs, HPV vaccination programs, and creation of cancer treatment centers. However there still exists a policy to practice gap and clinicians do not routinely screen for cancers and sensitization messages are not reaching those who need it most. Therefore, on the one hand the clinicians are not supplying these services and the women who need the services are not demanding for them. Methods: We used existing guidance for cervical and breast cancer screening and treatment including local policies and ASCO guidelines. We screened 64 women in the Ntasen and Ntanka communities of Cameroon. We then used the results to create sensitization and education programmes for community members using culturally relevant approach of storytelling. Results: We reported 11 out of 64 positive cervical conditions (VIA pos = 8; VILI pos = 10; both VIA/VILI pos = 7) making a 17.2% prevalence. The median age for VIA/VILI positive was 35.5 years (Range 21-60 years). 3 out of 11 (27.3%) were HIV positive. We reported 4 out of 64 positive breast conditions (BIRADS 2 (2); BIRADS 3 (1); BIRADS 4 (1)). We reported 12 out of 64 STIs (gonorrhea (4); Syphilis (2); HPV (6)). Treatment could not be initiated for breast and cervical conditions due to lack of health technologies needed. Patients were therefore referred for treatment. All participants with gonorrhea and syphilis were immediately initiated treatment. Conclusions: Considering the high burden of disease from cervical and breast cancer in Cameroon, Africa, and LMIC, exploring cost effective approaches for screening like VIA/VILI will be helpful in reducing disease burden. However, access to low-cost health technologies to provide treatment for positive cases, use of culturally relevant approaches to sensitize communities to uptake these health technologies, inclusion of patient representatives in decision making, and capacity building for clinicians and community health workers for diagnosis and treatment are needed to complete the recipe for conquering cancers in LMIC. A combined approach of routinely screening for breast, cervical, and STIs is useful for integrating a common cause for these conditions.
Attribution of symptoms to adjuvant endocrine therapy and association with adherence among older women with breast cancer: A qualitative study.
Authors: Amy Yoonjin Lee, Anna Lyons, Sailaja Kamaraju, Melinda Stolley, Joan Marie Neuner, Kathryn E. Flynn
Journal: Journal of Clinical Oncology (2022)

e24086 Background: Oral adjuvant endocrine therapy (AET) is an effective treatment for hormone receptor positive breast cancer to decrease recurrence and mortality. However, adherence to AET is poor, with 1/3 of patients not completing the recommended 5-year treatment course. Studies have shown that symptoms of the medication, such as joint pain, hot flashes, and fatigue, are associated with AET discontinuation. While previous studies have focused on symptoms post-AET initiation, preliminary evidence suggests that pre-AET symptoms may be an important predictor of early AET discontinuation. We used qualitative interviews to explore adherence to AET and patients’ attribution of symptoms to AET to provide context for a larger quantitative study on the role of patient-reported distress pre-AET as a predictor of AET discontinuation. Methods: Participants were recruited from the Froedtert/MCW Cancer Center registry, stratified by high (≥4) and low pre-AET Distress Thermometer scores and adherence to/discontinuation of AET. Semi-structured phone interviews followed an interview guide focused on constructs previously identified in the literature as having strong associations with AET adherence. Interviews were recorded and transcribed. A multidisciplinary team developed a codebook based on the conceptual framework describing AET discontinuation by AlOmeir et al. as well as other themes that emerged from the data. Results: Interviews were conducted with 31 participants; ages ranged from 57-86 years. Participants were diverse with respect to race/ethnicity (55% white, 26% Black, 13% Latina, and 6% other racial/ethnic groups). Participants who reported symptoms described hot flashes, joint pain, low appetite, memory loss, depression, and fatigue. We saw support for previous findings by AlOmeir et al in which ability to deal with symptoms affected the decision to continue AET. We uncovered additional nuance related to attribution of symptoms, in that some participants attributed their symptoms to a side effect of AET, while others attributed symptoms to other factors including older age, recent completion of other cancer treatments, and psychological burden associated with a cancer diagnosis and treatment. Those who did not attribute symptoms to AET focused on AET as necessary treatment to increase survival, while those who attributed symptoms to AET reported a more negative AET experience in general, with AET described as an additional burden after cancer. Conclusions: Symptom attribution rather than experience of specific symptoms may be a key factor leading to discontinuation of AET. Patient-reported symptoms and associated distress pre-AET may be a viable way to identify patients at high-risk for AET nonadherence, allowing for timely intervention. This will be quantitatively tested in a large sample.
Pharmacokinetic and pharmacodynamic activity evaluation of MAK683, a selective oral embryonic ectoderm development (EED) inhibitor, in adults with advanced malignancies in a first-in-human study.
Authors: Vincent Ribrag, Zev A. Wainberg, Lara Iglesias Docampo, Thiruvamoor Ramkumar, Louise Barys, Shuqi Chen, Marc Raccuglia, Mélanie Wilbaux, Karen Beltz, Amy Luyt, Yu Yun Fan, Naoko Suenaga, Fangjun Luo, Xuan Dai, Clinton Lai, Jia Chen
Journal: Journal of Clinical Oncology (2022)

3083 Background: Polycomb Repressive Complex 2 (PRC2) regulates transcription via trimethylation of histone H3 at lysine 27 (H3K27me3). Its dysregulation and over-expression are associated with tumorigenesis in several conditions. MAK683 is a potent oral inhibitor of PRC2 activation, allosterically targeting the EED–H3K27me3 binding site. Methods: NCT02900651 is an ongoing first-in-human dose-escalation study of MAK683 in adults with advanced malignancies. MAK683 was administered fasted once (QD) or twice daily (BID) on a continuous schedule in 28-day treatment cycles. The pharmacokinetic (PK) profile of MAK683 was assessed in sequential blood samples on Days 1, 8 and/or 15 of Cycles 1–6. MAK683 pharmacodynamic activity in Cycle 1, measured by change in H3K27me3, was evaluated in peripheral blood monocytes on Days 1, 8, and 15 by flow cytometry and in tumor biopsies at baseline and Day 15 by H-score. Results: As of Aug 30, 2021, 125 patients had received MAK683 at doses of 10–800 mg QD or 60–450 mg BID. MAK683 was well absorbed with a median T max of ̃1-4 hours across cohorts. PK exposure (C max , AUC) increased generally with dose over the entire dose range with no major deviation from dose proportionality, taking into account the sample size and PK variability. Apparent terminal half-life (geometric mean) was 2.5–6.6 hours across cohorts and constant over time. MAK683 accumulation of ̃0.9-2.2-fold (QD) or ̃1.3-2.0-fold (BID) was seen with repeat dosing. Peripheral monocytes showed substantial on-treatment reductions from baseline in the H3K27me3/H3 ratio across doses. Maximum percentage reduction was proportional to cumulative MAK683 AUC, with a trend towards greater reductions at higher baseline H3K27me3. H3K27me3 H-score reductions from baseline &gt; 40 were observed in 7/10 patients with diffuse large B-cell lymphoma (n = 4) or epithelioid sarcoma (n = 6) and paired baseline–Day 15 biopsies. RNA-seq characterization of biopsy samples is ongoing. Conclusions: MAK683 has a PK profile supportive of QD or BID dosing in patients with advanced malignancies. Analysis of H3K27me3 in blood monocytes and tumor biopsy confirm the in vivo pharmacodynamic activity of MAK683. Clinical trial information: NCT02900651.
Molecular predictors of response among patients with MMRd tumors treated on NCI-MATCH Arm Z1D.
Authors: Jonathan Daniel Schoenfeld, Nilofer Saba Azad, Jennifer Lee, Jacob Gross, Michael J. Overman, Katrina Kao, Anna Steinfeld, Donna Brunnquell, Xiangning Bu, Ping Guan, Jason L. Weirather, Kathleen L. Pfaff, Srin Ranasinghe, Victoria Wang, Peter J. O'Dwyer, Catherine J. Wu, Scott J. Rodig, David R. Patton, Lyndsay Harris
Journal: Journal of Clinical Oncology (2022)

2616 Background: On arm Z1D of the NCI-MATCH trial, the PD-1 inhibitor nivolumab was found to have activity among patients with mismatch repair-deficient (MMRd) tumors as defined by complete loss of MLH1 or MSH2 nuclear expression determined by immunohistochemistry, with 6-month progression free survival of 51%. We aimed to identify molecular predictors of response in this population. Methods: Among patients treated on NCI-MATCH Z1D, we evaluated genomic and tissue predictors of clinical benefit (CB), defined as patients with RECIST v1.1 complete or partial response or stable disease for ≥ 6months. WES files were processed and filtered using GATK best practices preceding TMB and MSI calculations according to MSI sensor score, a WES-based MSI rating system. Cutoffs were set to define TMB (TMB-Low: ≤10 mutation/Mb; TMB-High: &gt;10) and MSI (MSS: ≤10% unstable loci; MSI-Low: 10 &gt; x ≤ 20; MSI-High: &gt;20). Multiplex immunofluorescence (mIF) used formalin-fixed paraffin-embedded slides stained using a BOND RX automated stainer. Expression analyses followed normalization in DEseq2's median of ratios method. Gene set enrichment analysis was conducted by “empirical phenotype-based permutation test.” Additional RNA, WES, and mIF comparisons used the Wilcoxon rank-sum test. Results: Among 36 patients accrued to NCI-MATCH Z1D with pretreatment correlative samples available, 7 were unevaluable for response, and 1 was misclassified as having an MMRd tumor. Of the remaining 28, 15 had CB (2 CR, 10 PR, 3 SD ≤ 6 months) and correlative data were available for 26 (WES), 27 (RNAseq), and between 10-20 for mIF based on the marker assessed. According to MSI-sensor score, 11 were MSI-high, 8 were MSI-low, and 7 were MSS. MSI-sensor status, but not TMB was associated with CB (p=0.037 and p=0.185, respectively). Similar results were seen when using CR+PR vs SD+PD evaluation. Using RNAseq gene set enrichment analyses, CB patients had increased expression of interferon alpha (p=0.01), interferon gamma (p=0.03), PI3K-AKT-mTOR (p=0.02), cytotoxicity (p=0.05) and antigen processing (p=0.01) gene sets, while hedgehog signaling genes were increased in non-CB patients (p=0.04). The ESTIMATE immune index and infiltration of CD4+/PD1+/Ki67+ cell populations as determined by mIF were nominally higher in patients with CB (p=0.051 and p=0.075). Conclusions: Among patients with MMRd tumors treated with PD-1 checkpoint blockade, correlative analyses demonstrate associations between CB and MSI-sensor score as well as biomarkers indicative of immune infiltration and antigen presentation. This suggests that these measures may help differentiate patient response in MSI tumors. Clinical trial information: NCT02465060.
S100A7 as a founder of immunosuppressive tumor microenvironment shed light on immunotherapy in lung squamous cell carcinoma.
Authors: Chengming Liu, Sufei Zheng, Zhiliang Lu, Nan Sun, Jie He
Journal: Journal of Clinical Oncology (2022)

e20541 Background: The application of immune checkpoint inhibitors (ICIs) has revolutionarily improved the prognosis of patients with lung squamous cell carcinoma (LUSC) with limited treatment options, yet only certain patients can benefit from ICIs. S100A7 has been reported to accelerate tumor progression by activating oncogenic pathway in LUSC. Here, we aimed to deepen in the role played by S100A7 in the tumor immune microenvironment (TIME) and immunotherapeutic efficacy. Methods: Immunohistochemical analysis of PD-L1 expression and CD8 + tumor infiltrating lymphocytes (TILs) was applied to investigate the correlation between S100A7 expression and TIME. The mechanism of S100A7 regulating PD-L1 expression and infiltration of CD8 + TILs was then explored. Based on a mouse model and a clinical cohort, the association between S100A7 expression and the efficacy of ICIs was also analyzed. Results: Immunohistochemical analysis of 102 LUSC specimens revealed that S100A7 expression negatively corelated with PD-L1 expression and the infiltration of CD8 + TILs. The in vitro studies showed that S100A7 deregulated PD-L1 expression by activating the p-AKT pathway. Notably, a negative correlation between S100A7 expression and CXCL9 expression in tumor cell and CD68 + macrophage was observed in LUSC samples, which may lead to a decrease in CD8 + TILs. Results of murine models of LUSC revealed that dysregulation of S100A7 exerted an impact on anti-tumor response of immunotherapy. Further analysis showed that targeting S100A7 may enhance the efficacy of immunotherapy by yielding an inflammatory phenotype. In addition, baseline plasma level of S100A7 was higher in patients with progressive disease ( p = 0.0393) based on our cohort of LUSC patients treated with ICIs. The potential predictive value of baseline plasma level of S100A7 for immunotherapy response was then confirmed with area under curve up to 0.869. Multivariate Cox regression analyses revealed that baseline S100A7 level in plasma samples was an independent prognostic factor. Conclusions: This study deepened in the understanding of the role played by S100A7 in the TIME, offering a novel insight of its mechanism of action on immunotherapy resistance. Our results indicated that S100A7 may emerge as a powerful predictive tool for immunotherapy and the treatment targeting S100A7 may be beneficial for immunotherapy in LUSC.
Anlotinib for patients with recurrent or metastatic nasopharyngeal carcinoma: A phase II study.
Authors: Qingqing Cai, Ning SU, Yu Fang, Qihua Zou, Yi Xia, Shuyun Ma, Jun Cai, PanPan Liu, Jinni Wang, Yuchen Zhang
Journal: Journal of Clinical Oncology (2022)

e18020 Background: The prognosis of patients (pts) with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) is poor, especially for those who had failed two or more lines of prior systemic therapy. Anlotinib is a novel tyrosine kinase inhibitor that can inhibit tumor angiogenesis and proliferation by targeting VEGFR, FGFR, PDGFR, and c-Kit. A prospective, single-arm, phase 2 trial (NCT03906058) was performed to assess the efficacy and safety of single-agent anlotinib against R/M NPC and here we report the final results of this study. Methods: Eligible pts were aged 18-70 years old, diagnosed with histologically confirmed R/M NPC, had at least one measurable lesion and failed at least two lines of prior systemic treatments including chemotherapy, targeted therapy, or immunotherapy. Anlotinib was administered at 12 mg QD orally from day 1 to day 14 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was confirmed disease control rate (DCR). The second endpoints included confirmed objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. Tumor response was assessed according to RECIST 1.1 and adverse events were assessed according to NCI-CTCAE v5.0. Results: From April 2019 to March 2021, 39 pts were enrolled. 33 were male and 6 were female. The median age was 46.7 years (range, 20-64). 24 pts (61.5%) had liver metastasis. 29 pts (74.4%) had previously received 2 lines of systemic treatments and others received 3 or more. 19 pts (48.7%) pts had been exposed to anti-PD-1 immunotherapy. The median treatment duration of anlotinib was 4 cycles (range, 0.5-20). At the data cutoff date of Feb.1 st 2022, 36 pts have underwent tumor response evaluation and the best response to anlotinib was partial response for 8 pts and stable disease for 20 pts. The DCR was 77.8% and ORR was 22.2%. 28 patients have progressed. For the intent-to-treat population, the median PFS was 5.7 months (95% CI: 4.7-6.7). 21 pts have died and the median OS was 23.9 months (95% CI: 5.3-42.5). The most common treatment-related adverse event (TRAE) of any grade was hand-foot syndrome (HFS) (24 pts). Grade 3 TRAEs included HFS (9 pts), mucositis (7 pts), hypertension (21 pts), liver dysfunction (2 pts) and pneumonia (1 pts). Only one grade 4 TRAE (mucositis) was reported and no treatment-related death was observed. 13 pts experienced hemorrhage, all were grade 1 or 2. Conclusions: Anlotinib monotherapy seemed to be a promising option for pts with R/M NPC who were heavily treated. The survival benefits were impressive and the toxicity was tolerable. Clinical trial information: NCT03906058.